The specificities and numbers of lymphocytes in animals are tightly controlled to avoid autoimmunity and to avoid accumulation of lymphocytes generated during previous infections. This control can be achieved through the death of autoreactive lymphocytes as consequence of selection events. Similarly, many lymphocytes that are generated in response to infections die when the infectious agent disappears. The lymphocyte repertoire is also influenced by the ability of lymphocytes to alter their antigen receptor. For example, the antigen receptor expressed by some autoreactive lymphocytes can be modified either by deletion of the genes encoding the offending receptor, or by silencing the action of the autoreactive receptor. The numbers, specificities and activities of lymphocytes in animals are controlled, to avoid accumulation of the huge numbers of lymphocytes which are generated in each successive response to infection and to prevent autoimmunity. Several processes are used to achieve this control. Many of the lymphocytes which are generated in response to infections die when the infectious agent disappears. Some autoreactive lymphocytes die, others modify their receptors for antigen, either by deleting genes coding for the offending receptor, or by somehow silencing the action of the autoreactive receptor. Other autoreactive lymphocytes survive for a while as anergic cells and do not respond productively to antigen and have a shortened half life. The Projects in this Program will examine the ways in which lymphocytes are controlled, comparing the mechanisms used in different types of lymphocytes under different circumstances, with the goal of understanding how the immune system generates a useful but innocuous collection of antigen specific lymphocytes. The individual Projects will focus as follows: 1. On the role of bystander, non autoreactive receptors on B cells, and their ability to rescue cells bearing, in addition, autoreactive receptors from death. 2. On the generation and maintenance of anergic B cells, their specificities and the ability of infectious agents to allow these cells to escape anergy. 3. On the role of Bcl-2 related proteins in the death of activated T, and B cells. The Program has 4 Cores, all essential to the work on all Projects. The subjects of the Cores are: Flow Cytometry;Microscopy;Genetics and Administration.